Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics?

Abstract

Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.

Accurate lattice energies of organic molecular crystals from periodic turbomole calculations

“… Lowest energy conformations of the gas phase molecular structures of a) the rigid lactide, b) moderately flexible naproxen and c) highly flexible 3ClMA . [Color figure can be viewed at http://wileyonlinelibrary.com]…”

“…For (L)‐ and (DL)‐lactide the NAHNOZ ( Z ′=3, Z = 12, P212121) and BICVIS (Z′=1, Z = 4 P21/c) structures were retrieved, respectively. For the pure enantiomer of 3‐chloromandelic acid, ( S )‐3ClMA, the TUYBIA (Z′=2, Z = 4, P21) and for the racemic molecular compound ( R , S )‐3ClMA the FIZPEL03 ( Z ′=1, Z = 4, P21/c) crystal structures were used. Even though, ( S )‐3ClMA was shown to have a 2:1 disorder in the phenyl ring orientation only the pre‐dominant ( S )‐3ClMA orientation was used.…”

“…Such a process design requires an accurate knowledge of the thermochemistry of the crystalline forms of the pure enantiomers and their mixtures . Sometimes, the molecular association in solution does not correspond to that in the crystal . Computational methods are of increasing practical use here as their accuracy is converging to reproduce small enantiopure/racemic energy differences.…”

Is zeroth order crystal structure prediction (CSP_0) coming to maturity? What should we aim for in an ideal crystal structure prediction code?

“…63 It is noteworthy that despite extensive polymorph screening, a signicant number of drugs are being marketed on the false assumption (as shown by CSP_0) that they are in the most stable thermodynamic form (DOI: 10.1039/c8fd00069g). Predicting polymorphs that could never be found also has major industrial implications (DOI: 10.1039/ c8fd00033f).…”

Pilot Therapeutic Protocol for the Treatment of Local Advanced Disease, such as the Generalized Peritoneal Carcinomatosis and for the Treatment of Distant Metastases in Human Malignant Neoplastic Disease-Targeting the Medium

“…From those, conglomerates have always higher melting point from their enantiomeric analogues (Carnelley's law), especially with higher molecular symmetry, while the freezing point varies according to the racemic solution and its crystallization type. Thus, special research interest is focused primarily at the in vitro study of the crystallization type of the solutions of racemic mixtures from natural cancer proteins from various malignant neoplasms with their synthetic enantiomers, regarding the increase of their freezing point and their crystallization at higher temperature from that required for the crystallization of natural cancer protein solutions [2][3][4][5][6][7][8].…”